Controlled release pharmaceutical composition

ABSTRACT

A sustained/prolonged release pharmaceutical dosage form is disclosed. The form comprises a hard shell capsule and a formulation comprising (a) a water insoluble medicant, (b) a high melting fatty ester, (c) a low viscosity oil, (d) a cellulosic polymer, and (e) a non-ionic surfactant.

This is a division of Ser. No. 09/790,239, filed Feb. 21, 2001.

BACKGROUND OF THE INVENTION

One of the most frequently utilized methods to extend the duration ofdrug action in the body is by modification of the pharmaceutical dosageform. This is usually achieved with single or multicomponent matrixsystems such as granules, pellets, tablets or a combination of the abovewhere the drug delivery is mainly controlled by diffusion or erosionmechanisms.

Another commonly used procedure to sustain or control the rate of drugrelease is by utilizing polymer coating technology. Polymers with pHdependent or independent properties are coated onto the different dosageforms utilizing fluid bed or conventional coating equipment.

The delivery systems described above, traditionally have been used tomanufacture many of the available pharmaceutical dosage forms in themarket. However, for drugs that present a low melting point or aremetastable at room temperature the only available solid oral unit dosageform has been the soft gelatin capsule.

Soft gelatin encapsulation is rather a complex process and usuallyrequires the services of an outside contractor. However, manypharmaceutical companies would prefer to keep development activitiesin-house for reasons of confidentiality and control over the developmentprocess. With the new advances in pharmaceutical equipment technology itis now possible to formulate drug substances into semi-solid, liquid orpaste-like form for filling into hard-shell two piece capsules. Thistype of formulation technology demonstrates an alternative for thedifficult to manufacture soft gelatin technology and the ability tomaintain the development activities in-house.

There are several advantages that can be obtained by formulating drugsin liquids and/or semisolid (molten) formulations to be filled into hardshell two piece capsules. These are the ability to formulate with lowmelting point materials, low-dosed or highly potent drugs, compoundsthat are oxygen- or moisture sensitive, and for drugs that requirebioavailability enhancement.

Many of the liquid formulations in hard-shell capsules provide animmediate or fast release. This is usually achieved as a result of theimmediate release of the contents due to the fast disintegration time ofthe gelatin at body temperature. Other formulations utilize sustainedrelease liquid-filled release capsules utilizing thermosofteningmatrices. The excipients most frequently utilized are the Gelucires®,Gattefosse®, France, since they are available as semisolids with a widerange of melting points and HLB values. This variety allows flexibilityin mixing, adequate filling viscosity, different degrees ofbioavailability enhancement and a sustained drug release from thesemisolid matrix.

High melting glycerides have frequently been used as lubricants whenformulating tablets or capsules. Lubricants have a great effect on theaspect of the finished product and the ejection of the tablet out of thedie is improved. Lubricants are usually hydrophobic substances and whenused in high amount can alter the desegregation time of the tablet thusdelaying the bioavailability of the active ingredient.

The incorporation of lubricants (waxes, HMG) into tablet matrices hasbeen a popular method to prolong drug release. For example, sustainedrelease acetaminophen tablets with glyceryl behenate, Klucel HXF,hydroxy propyl cellulose (HPC), a swellable water-soluble polymer, andCarbopol® 934, a crosslinked polymer, has been prepared. It was observedthat all tablets containing a sustained release agent exhibited somedegree of prolonged drug release in vivo as compared to regular tablets.It was also noted that from all sustained release agents evaluated,glyceryl behenate provided the slowest release.

Glyceryl behenate as a potential controlled release wax matrix inspheres and tablets has been evaluated (10, 30 and 50%). At the 10%level no sustained action was observed. However, as the levels ofglyceryl behenate increased a significant slower release of the drug wasobtained. The results indicated that glyceryl behenate exhibited thepotential to create a controlled release matrix.

Sustained release preparations have also been achieved from other highmelting glycerides (glycerol palmitostearate and glyceryl monostearate).For example the release of theophylline embedded in a glycerolpalmitostearate matrix containing varying amounts of mannitol and/orhydroxypropyl methyl cellulose 4000 (HPMC) was evaluated. The release oftheophylline was modulated by varying the fraction of HPMC and/ormannitol used. When both HPMC and mannitol were used the matrix systemdeveloped followed a first-order dissolution release.

In general, natural, synthetic and/or semi-synthetic polymers such ascellulose or acrylics derivatives, have been used in high quantities(>10%) to retard the release of many pharmaceutical active ingredients.Such polymers are not usually recommended to be utilized in smallquantities to retard the release of API.

SUMMARY OF THE INVENTION

A controlled release pharmaceutical formulation is disclosed. Theformulation comprises a matrix construct of a component selected from ahigh melting point fatty acid ester, an oil, a polymeric cellulosederivative, and a mixture of any of the foregoing, having a selectedmedicament associated therewith.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawing illustrates the invention. In such a drawing:

FIG. 1 is a graphical representation of the in vitro release oflovastatin using Compritol 888;

FIG. 2 is a graphical representation of the in vitro release oflovastatin using Precirol ATO5;

FIG. 3 is a graphical representation of the in vitro release ofhydroxyzine pamoate using low HLB sufactant;

FIG. 4 is a graphical representation of the in vitro release ofhydroxyzine pamoate using high HLB surfactant; and

FIGS. 5 and 6 are graphical representations of the dissolution profilesof nifedipine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a sustained or modulated pharmaceuticalformulation comprising (1) a selected water insoluble medicament ordrug, (2) a suitable construct with which the drug is associated, i.e.is encapsulated therewithin or being part of the construct. Theconstruct provides a modulated release of the associated, e.g.encapsulated, drug to the body of a patient, e.g. a human being oranother animal, when the construct is administered e.g. orally, to thepatient.

As used herein the term “a water insoluble medicament, drug or activeingredient” includes such medicament drug or active ingredient that is(1) a sparingly soluble in water, i.e. 1 part solute into about 30 toabout up to about 100 parts of water; (2) “slightly water soluble”, i.e.1 part of solute into about 100 to up to about 1,000 parts of water; (3)“a very slightly water soluble”, i.e. 1 part of solute into about 1000to up to about 10,000 parts of water; and (4) “practically waterinsoluble”, i.e. 1 part of solute to at least about 10,000 parts ofwater; as defined in USP XXII.

The formulation is intended to be administered orally to the patient ina dosage form comprising a hard shell capsule filled with theformulation.

Suitable therapeutic medicament categories of drugs or medicaments arethose which are water insoluble and include cardiovascular drugs,antiallergics, analgesics, bronchodilators, antihistamines,antitussives, antifungals, antivirals, antibiotics, other painmedicaments, antiinflamatories, etc. Particularly suitable medicamentsinclude hydroxyzine pamoate; dihydropyridine calcium channel blockers,e.g. nifedipine, nimodipine, nisoldipine, nicardipine, amoldipine, etc.;statins e.g. atorvastatin, simvastatin, lovastatin, etc.,anticonvulsants, e.g. phenytoin, carbamezepine, etc.; analgesics, e.g.ibuprofen, naproxen, indomethacin, etc.steroids, e.g. prednisone,prednisolone, hydrocortisone, etc.; fibrates, e.g. gemfibrozil,fenofibrate, clofibrate, etc.; vitamins, e.g. vitamins A, D, E and K,etc.

For purposes of the formulations of this invention, which are intendedfor incorporation into a hard shell capsule unit dosage form, thebiotherapeutic medicament or drug is associated with the constructcarrier with which it is destined to be combined. By “associate” or“associated” is meant that the water insoluble medicament is present asa matrix or a part of the matrix along with the component making up theconstruct or is encapsulated within the carrier matrix, or is on thesurface of the carrier matrix.

A suitable construct is selected. Such a construct is one which willincorporate or encapsulate the selected medicament and provide acontrolled or modulated release of the medicament therefrom to the sitesof action or application to the patient's body, e.g. to thehepatobiliary receptors of the human being or other animal.

A suitable carrier construct comprises a material or component selectedfrom the group comprising a high melting fatty acid ester, such as forexample glyceryl behenate, gyceryl palmitosterate and glycerylstearate;low viscocity oils, e.g. vegetable oils, hydrogenated vegetable oils,corn oil, cottonseed oil, menhaden oil, safflower oil, sesame oil,shark-liver oil, soybean oil, olive oil and wheat germ oil; saturated,polyglycolyzed, glycerides, a cellulosic polymer, e.g. methocel Eseries, methocel A series, methocel K, series ethocel P series,low-substituted hydroxypropyl ether cellulose polymers, L H seriesmethocel and a mixture of any of the foregoing.

A most preferred cellulosic polymer is a methylcellulose polymer havinga structure,

which are conmmercially available from the Dow Chemical Company,Midland, Mich., under the tradename “METHOCEL”. e.g. METHOCEL A. Anothermost preferred cellulosic polymer is a hydroxypropoxyl methyl cellulosepolymer having a structure,

which are commercially available (Dow Chemical Company) under thedesignations METHOCEL E, METHOCEL F. METHOCEL and METHOCEL K brandproducts. Preferably, the formulation comprises a mixture of at leasttwo of the foregoing components.

The dosage form comprising a hard shell capsule utilizes theformulation, i.e. the construct or the matrix having the medicamentassociated therewith. Preferably, the sustained/prolonged releasepharmaceutical unit dosage form comprises the matrix or constructformulated from a mixture of the above-described materials orcomponents.

The high melting fatty acid esters (high melting glycerides) of theformulation and the sustained/prolonged release capsule unit dosageforms of the present invention comprise esters of fatty acids andpolyhydric alcohols, such as glycerol, melting at elevated temperatureswithin the range of from about 50° to about 80° C. The melting points offatty acid esters of behenic acid (docosanoic acid), palmitostearic acidand stearic acid and glycerol fall within this range and are suitablefor the formulations and unit dosage forms of the present invention.Other high melting fatty acid esters, that is, fatty acid esters meltingwithin the range (about 50° to about 80° C.), may be employed in theformulations and dosage forms.

The oils of the formulations and the sustained/prolonged release capsuleunit dosage forms of the present invention comprise triglycerides offatty acids having short (12 to 14 carbon atoms), medium (16 to 18carbon atoms) and long (18 to 22 carbon atoms) carbon chains and no, orup to 6 double bonds. Exemplary fatty acids are lauric acid (12 carbonatoms, no double bonds), myristic acid (14 carbon atoms, no doublebonds), palmitic acid (16 carbon atoms, no double bonds), palmitoleicacid (16 carbon atoms, one double bond), stearic acid (18 carbon atoms,no double bonds), oleic acid (18 carbon atoms, 1 double bond), linoleicacid (18 carbon atoms, 2 double bonds), eicosapentaenoic acid (20 carbonatoms, 5 double bonds (“EPA”) and docosahexanoic acid (22 carbon atoms,6 double bonds), which are found in various animal and vegetable oilslisted in the Table below.

TABLE Super Refined ® Oils and the Associated Typical Fatty AcidDistribution (%) Super Refined Product Myristic Palmitic PalmitoleicStearic Oleic Linoleic Linolenic EPA DHA Corn 1 10 0 3 30 55 0 0 0Cotton- 1 24.5 0 2.5 17 55 <1 0 0 seed Menhaden 8.5 23 12.5 3 12.5 2 <112 8.5 Olive 0 11.5 1 2 75 9.5 0 0 0 Peanut 0 7.5 1 4.5 62 20 0 0 0Safflower 0 7 0 3 15 75 0 0 0 Sesame 0 8 0 4.5 43 41 0 0 0 Shark-liver 212 7 4 30 6 5 4 4 Soybean 0 9 0 4 24 52 8 0 0 Wheat- 0 13.5 0 3.5 1954.5 7 0 0 germ

The cellulosic polymers of the formulations and sustained/prolongedrelease capsule unit dosage forms of the present invention compriseglucose polysaccharide ethers having multiple glucose units and methyl,ethyl, hydroxyethyl, hydroxypropyl or hydropropyl methyl substitution.Exemplary cellulosic polymers having methylether substitution are theMethocels, i.e., methocel E10, methocel A4M, methocel K15M, methocelK100LY and methocel K100M, and the Ethocels, for example, ethocel P20and low-substituted hydroxypropyl ether cellulose polymers LH11, LH22and LH30.

Surfactants which may optionally be employed with the formulations andsustained/prolonged release capsule unit dosage forms of the presentinvention, comprise polysorbates, such as ethers of polyoxyethylenesorbitan and fatty acids. Exemplary surfactants are polysorbate 80 andpolyoxyethylene 20 sorbitan monoleate, polyoxyxethylene alkyl ethers ofthe Brij- or Volpo series, Cremophor RH, Cremophor EL, polyoxyethylenesorbitan fatty acid esters of the Tween- or Crillet series,polyoxyethylene stearates of the Cerosynt- or Myrj series, lecithin,poloxamers, d-2-tocophenyl polyethylene glycol 1000 succinate (Vitamin ETPGS) and saturated polyglycolized glycerides (Labrasol, Labrafil andGelucires),polyoxyethylene castor oil derivations, such as polysorbate80 which is preferred.

The release of the insoluble or partially water soluble activeingredient or drug of the pharmaceutical unit dosage forms of thepresent invention is sustained over a prolonged period of about 24hours. The sustained release of the water insoluble medicament from ahard shell capsule is dependent upon the type and amount of medicament,the high melting fatty acid ester, cellulose polymer and a surfactant(if employed).

The most preferred formulation comprises a water insoluble medicament,and a mixture comprising glyceryl behenate as the fatty acid ester, anoil, a cellulosic polymer, such as for example, a methyl or ethyl etherof a cellulose, e.g., a methocel or an ethocel, and polysorbate 80surfactant.

Optionally, pharmaceutically acceptable excipients, compatible with therequirements for filling the capsules that the formulation be in thefluid state, i.e., a liquid or semi solid, at the filling temperature,may be included in the formulation. Such excipients comprise asurfactant, such as for example polysorbate 80;stabilizers/antioxidants, such as for example butylated hydroxytoluene,propyl gallate, vitamin E, ascorbic acid and ethylene diaminetetraacetic acid; solubilizers, such as for exampleN-methyl-2-pyrrolidone, citrate esters, e.g., Citroflex 2, acetylatedmonoglycerides, e.g., Triacetin and Mygliols; viscosity modifiers, suchas for example polyethylene glycols, e.g. PEG, and silica derivatives,e.g., silicon dioxide; and fillers such as for example hydrocarbons,e.g., paraffin and mineral oil. Preferably, combined with the componentor components of the carrier and the drug is a surfactant, such aspolysorbate 80.

The release of water insoluble medicaments from the unit dosageformulation generally depends on the type and amount of the high meltingfatty acid in the formulation and varies substantially with the type andamount thereof. For example, the release of lovastatin from aformulation containing the same cellulose (methocel) component over aprolonged period of about 24 hours, is fastest with Precirol AT05,slowest with Compritol 888. The release of Lovastatin/Ethocel from aformulation of the precirol is moderately faster as the same formulacontaining compritol and ethocel.

The release of water insoluble medicament from a unit dosage formulationis markedly dependent on the type and amount of the cellulosic polymer.For example, lovastatin, compritol, is released considerably faster froma formulation of Methocel K100M than Ethocel P20. Similarly,lovastatin/precirol is released from a unit dosage formulation fasterwhen the formulation contains Methocel K100M than Ethocel P20.

The formulations of the water insoluble medicaments of the presentinvention are useful for encapsulation in hard shell capsules for oraladministration for the treatment of various diseases and disorders, forexample, lovastatin, as an antilipidimic, or nifedipine as anantihypertensive agent, hydroxyzine pamoate as a antihistamine. Thedrugs are readily available from commercial suppliers.

The high melting fatty acid esters, the oils, the cellulosic polymersand surfactants and other excipients of the formulations of the presentinvention suitable for encapsulation in hard shell capsules aregenerally available from commercial sources. The water insolublemedicaments are also commercially available. Pharmaceutically acceptableacids and bases required for salt formation of water insolublemedicaments are available from suppliers such as Aldrich ChemicalCompany, Milwaukee, Wis.

The sustained/prolonged release pharmaceutical unit dosage forms areprepared by fluidizing matrix carrier material or components, e.g. ahigh melting fatty acid ester, an oil, a cellulosic polymer or a mixtureof the foregoing, to provide a formulation, to which is added themedicament which dissolves therein, which is then filled into a hardshell capsule, while in the fluid state, and, generally, allowed tosolidify in the capsule. The filling of the hard shell capsule isconveniently performed by a capsule filling machine for liquid fillingof the type available, for example, from Robert Bosch GmbH, (Hofligenand Kars GKF/L Series), Germany, Harro Hoefleger GmbH, (KFM/L Series),Germany, or Zanasi Nigris SpA (AZ 20/L Series), Italy. The hard shellcapsules are generally sealed by one of several methods. The filledcapsule may be sprayed with a water alcohol mixture to seal the cap tothe body of the container. Alternatively, the cap may be sealed to thebody of the container by a bonding process, which entails passing thecap over a revolving wheel immersed in a water gelatin or a cellulosebath and then passing the capsule through a drying chamber to seal thegap between the cap and the body of the capsule with dried gelatin orcellulose. The bonding is generally performed on commercially availablemachines manufactured by Robert Bosch GmbH and Zanasi Nigris SpA, makersof capsule filling machines.

Empty hard shell capsules are commercially available from the CapsugelDivision of Warner-Lambert Co., Greenwood, S.C., and from ShionogiQualicaps, Whitsett, N.C., in various sizes to accommodate the dosagerequirements for the treatment of disease or disorder states. Forexample, size 0 may be employed for unit dosage forms for potent drugformulations whereas size 000 would be required for a less potent drug,depending on the amounts of the components of the formulation andexcipients.

Gelatin and hydroxypropylmethylcellulose (HPMC) capsules may be used ascontainers for the formulations. Hydroxypropylmethylcellulose capsulesare preferred.

The following examples are illustrative and do not define the scope ofthe invention described and claimed herein.

EXAMPLES General Example

The sustained/prolonged release formulations of the present inventionare generally prepared by heating the matrix component or componentsuntil liquid (a melt), usually at the capsule filling temperature(70-90° C.) and adding the water insoluble medicament to the melt. Theamount of water insoluble medicament utilized in all formulations isabout 20% of the total amount of the formulation. Size #0 Hard-Shellhydroxypropylmethylcellulose capsules are utilized since they are heatresistant. In order to assure proper mixing and to reduce the amount ofair entrapped with stirring (vortex created), batches containing aminimum of 50 grams are prepared. A general formulation is illustratedbelow.

Ingredients % Qty (g) Medicament  20.0 10.00 High Melting Glyceride 25.0 12.50 Surfactant  1.0  0.50 Cellulose Polymer  3.0  1.50 Vegetableoil  51.0 25.50 Total 100.0 50.00

Example 1

Soybean oil, polysorbate 80, and Compritol 888 in the amounts shown inTable 1 were weighed and placed in a glass beaker. The mixture washeated to 75-80° C. until the contents melted by immersing the beakerinto a water bath heated by a Hot-Plate. The melt in the amount shown inTable 1 below was stirred with a laboratory mixer fitted with a straightblade propeller to disperse the ingredients and create an homogeneousmelt. To the melt, Methocel E or Ethocel 10P was slowly added withheating and stirring. After addition of the Methocel E 10P was complete,the melt was cooled to approximately 70° C., and then cooled atapproximately 70° C., the water insoluble medicament lovastatin, wasslowly added, and the melt was stirred until uniform. Capsules size 0were filled with 500 mg of melt, with a pipette. The filling weights ofeach capsule were recorded to guarantee consistency. The melt was allregular type maintained at approximately 70° C. during the fillingprocess. The release of the medicament, lovastatin, was then determined.

The dissolution release of the formulations was determined by the USPBasket Method (Apparatus 1). By this method, samples are tested in a 40mesh basket rotating at 100 RPM. Release media were used in a volume of900 Ml per dissolution vessel, maintained at 37° C. Double distilleddeionized water with 1% sodium dodecyl sulfate was generally used as thedissolution media. Nine samples of 3.0 ml each were automaticallycollected at 2, 4, 6, 8, 10, 12, 14, 20 and 24 hours. The absorbency ofthe samples was measured at the peak wavelength in the ultravioletspectrum with Hewllet Packard model 8453 spectrophotometer. Theabsorbency values were converted to percentages of added medicament thatwas released.

FIG. 1 shows the in vitro release of lovastatin using Compritol 888 anddifferent cellulose products in the capsule system. The Methocelproducts differ in their chemical substitution attached to its cellulosebackbone. The chemical substituents are hydroxypropoxyl and methoxylgroups. The methoxyl substituent provides more hydrophobicity and doesnot contribute to a great extent to the hydrophilic nature of thecellulose polymer thus having minimal influence on the rate of polymerhydration. On the other hand, the more hydrophilic hydroxypropoxyl groupdoes contribute greatly to the rate of polymer hydration. Consequently,Methocel K products have the fastest rate of hydration than the otherpolymers due to its higher amount of the hydroxypropoxyl groups and alower amount of the hydrophobic methoxyl group. Methocel E has a highercontent of methoxyl group than hydroxypropoxyl groups attached thusproviding a slower rate of hydration. Ethocel is a water insolublepolymer, with the same cellulose backbone and no water hydratingproperties. The polymer is only organosoluble. The results show that forall formulas evaluated a sustained release of the drug was obtained. Thefastest hydrating polymers provided a faster release thus allowingmodulation of the sustained release effect. (Methocel K>MethocelE>Ethocel).

TABLE 1 Formula/ Ingredients 1 2 3 Lovastatin 20.0 20.0 20.0 Compritol888 25.0 25.0 25.0 Methocel E10P 3.0 Methocel K100M 3.0 Ethocel P20 3.0Olive Oil 51.0 51.0 51.0 Polysorbate 80 1.0 1.0 1.0

Example 2

Following the procedure of Example 1, using the amounts of thecomponents shown in Table 2 below, hard shell capsules of theformulations were obtained. The release of the medicament was determinedby the procedure of Example 1, and the results are recorded graphicallyin FIG. 2.

FIG. 2 shows the in vitro release of lovastatin using Precirol ATO5 anddifferent cellulose based products in the capsule system. Precirol ATO5has a lower melting point than Compritol 888 due to shorter fatty acidchains. Compritol 888 which is glyceryl behenate contains a 22 carbonfatty acid length chain. Precirol ATO5 is an equal mixture of thepalmitate and sterate, 16 and 18 carbon units respectively. The use of alower melting glyceride resulted in faster dissolution profiles of thewater insoluble lovastatin. For systems containing the fast hydratingMethocel polymers, lovastatin was completely released in 4 hours. Forsystems containing the non-hydrating Ethocel a sustained release of thelovastatin was obtained over 24 hours. It is clearly demonstrated thatthe dissolution release is dependent on the type of polymer used.

TABLE 2 Fomula/Ingredients 1 2 3 Lovastatin 20.0 20.0 20.0 Precirol ATO5 25.0 25.0 25.0 Methocel E10 P 3.0 Methocel K100M 3.0 Ethocel 3.0 OliveOil 51.0 51.0 51.0 Polysorbate 80 1.0 1.0 1.0

Example 3

This example illustrates the release of the active pharmaceuticalingredient hydroxyzine pamoate. In order to optimize the inclusion ofthis water insoluble salt in the capsule semisolid matrix, severalsurfactant classes and levels were evaluated (1-10% by weight). Atlevels lower than 2% by weight significant sample to samplevariabilities were observed in the dissolution profiles indicating thatthe matrix was not well dispersed or a non-homogeneous mixture wasobtained. Since excessive amounts of surfactant are not recommended fororal intake, the smallest amount which provides minimal sample to samplevariability was evaluated (2% by weight level). These formulationslisted in Table 3 below were prepared by melting the Compritol 888 withLabrasol and the specified surfactant in a suitable size beaker. Thetemperature of the mixture was kept at 75-80° C. with the aid of aheated plate and water bath. The mixture was constantly mixed until itbecame homogeneous. Once the mixture was homogeneous and free of anyagglomerates, the cellulose polymer was added slowly to the melt withcontinuous mixing. The temperature of the mixture was then lowered toapproximately 70° C. Once the mixture cooled to approximately 70° C.,the hydroxyzine pamoate was slowly dispersed. The final melt was mixedwell until uniform. Utilizing an appropriate pipette HPMC Capsules (#0)were filled with 500 mg of the melted mixture. The liquefied meltimmediately solidified at room temperature. The actual filling weightswere recorded for each capsule. Empty capsules were tared and balancezeroed. The melt mixture was maintained at approximately 70° C. duringthe filling operation.

The results of combinations utilizing a low HLB surfactant are shown inFIG. 3. The results utilizing a high HLB surfactant are shown in FIG. 4.

Formula/Ingredients 1 2 3 4 Hydroxyzine Pamoate 20.0 20.0 20.0 20.0Compritol 888 25.0 Methocel K100 3.0 3.0 Methocel E10 P Ethocel 3.0 3.0Precirol ATO 5 25.0 Labrasol 51.0 51.0 51.0 51.0 Polysorbate 80 2.0 2.02.0 2.0

Example 4

This example further illustrates the modulated sustained releasebehavior of nifedipine. Nifedipine is a calcium channel blocking agentindicated for the management of hypertension and other cardiovasculardiseases. Extended release tablets are available at 60 and 90 mg doses.In order to adjust for the proper and recommended dosing, the filledweight of the capsules was reduced to 450 mg. At a 20% medicament leveleach capsule will contain a total of 90 mg nifedipine. The proceduresused to manufacture the capsules were the same as those described inExample 1. The formulation and the percentages for each are described inTable 4—below. The dissolution profiles demonstrating the modulatedsustained release effect of the capsule matrix and the effect of thepolymer and surfactant combinations are seen in FIGS. 5 and 6.

TABLE 4 Formula/Ingredients 1 2 3 4 Nifedipine 20.0 20.0 20.0 20.0Compritol 888 25.0 Methocel K100 3.0 3.0 Methocel E10 Ethocel 3.0 3.0Precirol ATO 5 25.0 Labrasol 51.0 51.0 51.0 51.0 Polysorbate 80 2.0 2.02.0 2.0

We claim:
 1. A modulated release pharmaceutical construct whichcomprises a matrix of a material comprising (a) a high melting fattyacid ester, (b) an oil, (c) a cellulosic polymer, and a water insolublemedicament associated with said matrix; wherein said water insolublemedicament is a medicament selected from the group consisting ofhydroxyzine pamoate, nifedipine, nimodipine, nisoldipine, nicardipine,amoldipine, atorvastatin, simvastatin and lovastatin, genfibrozil,fenofibrate and clofibrate.
 2. The construct as defined in claim 1wherein the matrix further comprises a surfactant added to saidmaterial.
 3. The construct as defined in claim 1 wherein the matrix isformed from a mixture comprising said ester selected from the groupconsisting of glyceryl behenate, glyceryl palmitostearate and glycerylstearate; said oil selected from the group consisting of corn oil,cottonseed oil, menhaden oil, safflower oil, sesame oil, shark-liveroil, soybean oil, olive oil, wheat grain oil; and said polymer selectedfrom a low substituted hydroxypropyl ether cellulosic polymer.
 4. Theconstruct as defined in claim 3 wherein said mixture further comprises asurfactant comprising a non-ionic surfactant.
 5. A sustained releasepharmaceutical composition comprising: a construct comprising (a) a highmelting fatty acid ester, (b) an oil, (c) a cellulosic polymer, and awater insoluble medicament associated with said construct; wherein saidwater insoluble medicament is a medicament selected from the groupconsisting of hydroxyzine pamoate, nifedipine, nimodipine, nisoldipine,nicardipine, amoldipine, atorvastatin, simvastatin and lovastatin,gelpfibrozil, fenofibrate and clofibrate.
 6. A sustainedrelease/prolonged release pharmaceutical unit dosage form comprising:(a) a hard shell capsule; (b) a carrier construct having a matrix of amaterial comprising (a) a high melting fatty acid ester, (b) an oil, (c)a cellulosic polymer and a water insoluble medicament associated withsaid matrix, wherein said water insoluble medicament is a medicamentselected from the group consisting of hydroxyzine pamoate, nifedipine,nimodipine, nisoldipine, nicardipine, amoldipine, atorvastatin,simvastatin and lovastatin, gefibrozil, fenofibrate and clofibrate.
 7. Aprocess for preparing a sustained/prolonged release pharmaceutical unitdosage form, which comprises: (a) fluidizing a carrier comprising (a′) ahigh melting fatty acid ester, (b′) an oil, (c′) a cellulosic polymer,to form a carrier solution; (b) adding a water insoluble medicament tosaid carrier solution to form a medicament solution; wherein said waterinsoluble medicament is a medicament selected from the group consistingof hydroxyzine pamoate, nifedipine, nimodipine, nisoldipine,nicardipine, amoldipine, atorvastatin, simvastatin and lovastatin,gemfibrozil, fenofibrate and clofibrate, (c) transferring saidmedicament solution to a hard shell capsule to solidify said medicamentsolution to form the dose having a component matrix with said medicamentassociated therewith.